4.7 Article

Hypoxic Conditions Promote the Angiogenic Potential of Human Induced Pluripotent Stem Cell-Derived Extracellular Vesicles



DOI: 10.3390/ijms22083890


extracellular vesicles (EV); induced pluripotent stem cells (iPSC); hypoxia; angiogenesis; regenerative medicine; hypoxia-inducible transcription factor (HIF)


  1. European Union's Horizon 2020 research and innovation program [733006, 731377]
  2. Land Salzburg Cancer Cluster Salzburg-Smart Specialization Center (CCS) [20102-P1601064-FPR01-2017]
  3. Land Salzburg/IWB/EFRE 2014-2020 Transfer Center for Extracellular Vesicles Theralytic Technologies (EV-TT) [P1812596]
  4. Land Salzburg/WISS, EV-TT-Bpro (Begleitprojekt zu IWB Zentrum EV-TT) [2025 20102-F1900731-KZP]
  5. German Research Foundation (DFG) [REBIRTH EXC 62/2, ZW64/4-1, KFO311/ZW64/7-1]
  6. German Ministry for Education and Science (BMBF) [13N14086, 01EK1601A, 01EK1602A, 13XP5092B, 031L0249]
  7. Forderung aus Mitteln des Niedersachsischen Vorab [ZN3340]
  8. European Union H2020 project TECHNOBEAT [66724]
  9. H2020 Societal Challenges Programme [731377] Funding Source: H2020 Societal Challenges Programme

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The study found that the quantity of iPSC-EVs is influenced by oxygen conditions and the method of EV preparation, with the best recovery observed at 1% oxygen and significantly elevated angiogenic potential.
Stem cells secrete paracrine factors including extracellular vesicles (EVs) which can mediate cellular communication and support the regeneration of injured tissues. Reduced oxygen (hypoxia) as a key regulator in development and regeneration may influence cellular communication via EVs. We asked whether hypoxic conditioning during human induced pluripotent stem cell (iPSC) culture effects their EV quantity, quality or EV-based angiogenic potential. We produced iPSC-EVs from large-scale culture-conditioned media at 1%, 5% and 18% air oxygen using tangential flow filtration (TFF), with or without subsequent concentration by ultracentrifugation (TUCF). EVs were quantified by tunable resistive pulse sensing (TRPS), characterized according to MISEV2018 guidelines, and analyzed for angiogenic potential. We observed superior EV recovery by TFF compared to TUCF. We confirmed hypoxia efficacy by HIF-1 alpha stabilization and pimonidazole hypoxyprobe. EV quantity did not differ significantly at different oxygen conditions. Significantly elevated angiogenic potential was observed for iPSC-EVs derived from 1% oxygen culture by TFF or TUCF as compared to EVs obtained at higher oxygen or the corresponding EV-depleted soluble factor fractions. Data thus demonstrate that cell-culture oxygen conditions and mode of EV preparation affect iPSC-EV function. We conclude that selecting appropriate protocols will further improve production of particularly potent iPSC-EV-based therapeutics.


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